Beta-hairpin peptidomimetics

ABSTRACT

These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of co-pending application Ser. No.14/781,229 filed on Sep. 29, 2015, which is a National Stage ofPCT/EP2014/056285 filed on Mar. 28, 2014, which claims priority toPatent Application No. 13001657.9 filed in Europe on Mar. 30, 2013. Theentire contents of each of these applications are hereby incorporated byreference.

The present invention provides β-hairpin peptidomimetics havingGram-negative antimicrobial activity and being embraced by the generaldisclosures of, but not specifically disclosed in, WO02/070547 A1 andWO2004/018503 A1.

The β-hairpin peptidomimetics of the invention are compounds of thegeneral formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²], andpharmaceutically acceptable salts thereof, with P¹ to P¹², T¹ and T²being elements as described herein below.

In addition, the present invention provides an efficient syntheticprocess by which these compounds can, if desired, be made in parallellibrary-format. Moreover, the β-hairpin peptidomimetics of the inventionshow improved efficacy, reduced hemolysis of red blood cells and reducedor no cytotoxicity.

A major cause of death worldwide and a leading cause of mortality indeveloped countries are infectious diseases. They result from thepresence of pathogenic microbial agents including pathogenic viruses andpathogenic bacteria. The problem of bacterial resistance to establishedantibiotics has stimulated intense interest in developing novelantimicrobial agents with new modes of action (D. Obrecht, J. A.Robinson, F. Bernadini, C. Bisang, S. J. DeMarco, K. Moehle, F. O.Gombert, Curr. Med. Chem. 2009, 16, 42-65; H. Breithaupt, Nat.Biotechnol. 1999, 17, 1165-1169).

A growing unmet medical need is represented by Gram-negative bacteriacausing 60% of nosocomial pneumonias (R. Frechette, Ann. Rep. Med.Chem., Elsevier, 2007, 349-64). Extended spectrum beta lactamase(ESBL)-producing Gram-negative bacteria have also compromised theutility of many front-line beta-lactam drugs (S. J. Projan, P. A.Bradford, Curr. Opin. Microbiol., 2007, 10, 441). The lack of suitablenew compounds is forcing clinicians to use previously discardedantibiotics like colistin, despite well-known toxicity problems (M. E.Falagas, S. K. Kasiakou, Crit. Care, 2006, 10, R 27). Therefore, novelapproaches are needed to treat inter alia resistant strains ofKlebsiella pneumoniae, Acinetobacter baumannii and Escherichia coli (H.W. Boucher, G. H. Talbot, J. S. Bradley, J. E. Edwards Jr, D. Gilbert,L. B. Rice, M. Scheid, B. Spellberg, J. Bartlett, IDSA Report onDevelopment Pipeline, CID 2009, 48, 1).

One emerging class of antibiotics is based on naturally occurringcationic peptides (T. Ganz, R. I. Lehrer, Mol. Medicine Today 1999, 5,292-297; R. M. Epand, H. J. Vogel, Biochim. Biophys. Acta 1999, 1462,11-28). These include disulfide-bridged β-hairpin and β-sheet peptides(such as the protegrins [V. N. Kokryakov, S. S. L. Harwig, E. A.Panyutich, A. A. Shevchenko, G. M. Aleshina, O. V. Shamova, H. A.Korneva, R. I. Lehrer, FEBS Lett. 1993, 327, 231-236], tachyplesins [T.Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M.Niwa, T. Takao, Y. Shimonishi, J. Biol. Chem. 1988, 263, 16709-16713],and the defensins [R. I. Lehrer, A. K. Lichtenstein, T. Ganz, Annu. Rev.Immunol. 1993, 11, 105-128], amphipathic α-helical peptides (e.g.cecropins, dermaseptins, magainins, and mellitins [A. Tossi, L. Sandri,A. Giangaspero, Biopolymers 2000, 55, 4-30]), as well as other linearand loop-structured peptides. Although the mechanisms of action ofantimicrobial cationic peptides are not yet fully understood, theirprimary site of interaction is the microbial cell membrane (H. W. Huang,Biochemistry 2000, 39, 8347-8352). Upon exposure to these agents, thecell membrane undergoes permeabilization, which is followed by rapidcell death. However, more complex mechanisms of action, for example,involving receptor-mediated signaling, cannot presently be ruled out (M.Wu, E. Maier, R. Benz, R. E. Hancock, Biochemistry 1999, 38, 7235-7242).

In the compounds described below, a strategy is introduced to stabilizeβ-hairpin conformations in backbone-cyclic cationic peptide mimeticsexhibiting broad spectrum Gram-negative antimicrobial activity. Thisinvolves transplanting the hairpin sequence onto a template, whosefunction is to restrain the peptide loop backbone into a hairpingeometry.

Template-bound hairpin mimetic peptides have been described in theliterature (D. Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441) and theability to generate β-hairpin peptidomimetics using combinatorial andparallel synthesis methods has now been established (L. Jiang, K.Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000,83, 3097-3112). Antibacterial templatefixed peptidomimetics and methodsfor their synthesis have been described in international patentapplications WO02/070547 A1, WO2004/018503 A1, WO2007/079605 A2 andWO2012/016595 A1 but these molecules do not show broad spectrumGram-negative antimicrobial activity having high potency againstKlebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichiacoli.

The present invention relates to novel β-hairpin peptidomimetics offormula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I)wherein the single elements T or P are connected in either directionfrom the carbonyl (C═O) point of attachment to the nitrogen (N) of thenext element and wherein

-   T¹ is a naturally or non-naturally occurring D α-amino acid    containing an optionally substituted side-chain which forms a    five-membered heterocycle, or a bicyclic system comprising the    α-carbon and the α-amino atom;-   T² is a naturally or non-naturally occurring L α-amino acid    containing an optionally substituted side-chain which forms a five-    or six-membered heterocycle, or a bicyclic system comprising the    α-carbon and the α-amino atom;-   P¹, P³ and P¹⁰ are independently    -   a naturally or non-naturally occurring aliphatic or aromatic L        α-amino acid containing in total 1 to 25 carbon- and/or        heteroatoms in a single side-chain;-   P² and P⁸ are independently    -   a naturally or non-naturally occurring aromatic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain;-   P⁴ and P⁹ are independently    -   a naturally or non-naturally occurring basic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain comprising at least one amino function; or    -   a naturally or non-naturally occurring alcoholic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain;-   P⁵ and P⁷ are independently    -   a naturally or non-naturally occurring basic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain comprising at least one amino function;-   P⁶ is a naturally or non-naturally occurring basic L or D α-amino    acid or cyclic α,α-disubstituted α-amino acid containing in total 1    to 25 carbon- and/or heteroatoms in a single side-chain comprising    at least one amino function;-   P¹¹ is a naturally or non-naturally occurring aliphatic or aromatic    L α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain; or a naturally or non-naturally    occurring L α-amino acid containing in total 1 to 25 carbon- and/or    heteroatoms in a single side-chain comprising at least one urea    function, amide function, ester function, sulfone function or ether    function; or a naturally or non-naturally occurring alcoholic L    α-amino acid containing in total 1 to 25 carbon- and/or heteroatoms    in a single side-chain;-   P¹² is a naturally or non-naturally occurring aliphatic containing    in total 1 to 25 carbon- and/or heteroatoms in a single side-chain;    or    -   a naturally or non-naturally occurring alcoholic L α-amino acid        containing in total 1 to 25 carbon- and/or heteroatoms in a        single side-chain;        or a tautomer or rotamer thereof, or a salt, or a hydrate or        solvate thereof.

A particular embodiment of the present invention relates to compoundsaccording to general formula (I), wherein

-   T¹ is an D α-amino acid residue of one of the formulae

-   T² is an L α-amino acid residue of one of the formulae

-   P¹, P³ and P¹⁰ are independently an L α-amino acid residue of one of    the formulae

-   P² and P⁸ are independently an L α-amino acid residue of formula

-   P⁴ and P⁹ are independently an L α-amino acid residue of one of the    formulae

-   P⁵ and P⁷ are independently an L α-amino acid residue of formula

-   P⁶ is an L or D α-amino acid residue of one of the formulae

-   P¹¹ is an L α-amino acid residue of one of the formulae

-   P¹² is an L α-amino acid residue of one of the formulae

-   R^(Alk) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, C₁₋₁₂-alkyl; C₂₋₁₂-alkenyl; cycloalkyl;    cycloalkyl-C₁₋₆-alkyl; or C₁₋₆-alkoxy-C₁₋₆-alkyl;-   R^(Ar) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R⁴)_(n)R¹⁹⁰; —(CH₂)_(n)O(CH₂)_(m)R¹⁹;    —(CH₂)_(n)S(CH₂)_(m)R¹⁹; or —(CH₂)_(n)NR¹⁴(CH₂)_(m)R¹⁹;-   R^(Am) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, heterocycloalkyl; heterocycloalkyl-C₁₋₆-alkyl;    —(CR¹R¹³)_(q)NR¹⁵R¹⁶; —(CH₂)_(q)C(═NR¹³)NR¹⁵R¹⁶;    —(CH₂)_(q)C(═NOR¹⁷)NR¹⁵R¹⁶; —(CH₂)_(q)C(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CR¹R¹³)_(q)NR²C(═NR¹⁷)NR¹⁵R¹⁶; —(CR¹R¹³)_(q)N═C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)O(CH₂)_(m)NR¹⁵R¹⁶; —(CH₂)_(n)O(CH₂)_(m)C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)C(═NOR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)C(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)O(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)O(CH₂)_(m)A═C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)S(CH₂)_(m)NR¹⁵R¹⁶; —(CH₂)_(n)S(CH₂)_(m)C(═NR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)S(CH₂)_(m)(═NOR¹⁷)NR¹⁵R¹⁶;    —(CH₂)_(n)S(CH₂)_(m)(═NNR¹⁵R¹⁶)NR¹⁷R¹⁸;    —(CH₂)_(n)S(CH₂)_(m)NR¹C(═NR¹⁷)NR¹⁵R¹⁶; or    —(CH₂)_(n)S(CH₂)_(m)N═C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-   R^(cAm) is, —(CH₂)_(n)NR¹⁵(CH₂)_(m)—;-   R^(Het) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R¹³)_(q)OR¹⁴; —(CR¹R¹³)_(q)SR¹⁵;    —(CR¹R¹³)_(q)SO₂R¹⁵; —(CR¹R¹³)_(q)SO₂NR¹R¹⁴;    —(CR¹R¹³)_(q)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(q)NR¹⁴SO₂R¹⁵;    —(CR¹R¹³)_(q)NR¹⁴SO₂NR¹⁵R¹⁶; —(CH₂)_(n)O(CH₂)_(m)OR¹⁴;    —(CH₂)_(n)O(CH₂)_(m)SR¹⁵; —(CR¹R¹³)_(q)COOR¹⁵;    —(CR¹R¹³)_(q)CONR¹⁵R¹⁶; or —(CR¹R¹³)_(q)NR²CONR¹⁵R¹⁶;-   R^(OH) is, with the proviso of containing less than 26 carbon-    and/or heteroatoms, —(CR¹R¹³)_(q)OH; —(CR¹R¹³)_(q)SH;    —(CH₂)_(n)O(CH₂)_(m)OH; —(CH₂)_(n)S(CH₂)_(m)OH;    —(CH₂)_(n)NR¹(CH₂)_(m)OH; hydroxy-C₁₋₈-alkyl; hydroxy-C₂₋₈-alkenyl;    hydroxy-cycloalkyl; or hydroxy-heterocycloalkyl;-   R¹, R² and R³ are independently    -   H; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; or aryl-C₁₋₆-alkyl;-   R⁴, R⁵, R⁶, R⁷ and R⁸ are independently    -   H; F; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;        heterocycloalkyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;        heteroaryl-C₁₋₅-alkyl; —(CHR¹³)_(o)OR¹⁵; —O(CO)R¹⁵;        —(CHR¹³)_(o)SR¹⁵; —(CHR¹³)_(o)NR¹⁵R¹⁶; —(CHR¹³)_(o)OCONR¹⁵R¹⁶;        —(CHR¹³)_(o)NR¹CONR¹⁵R¹⁶; —(CHR¹³)_(o)NR¹COR¹⁵;        —(CHR¹³)_(o)COOR¹⁵; —(CHR¹³)_(o)CONR¹⁵R¹⁶; —(CHR¹³)_(o)PO(OR¹)₂;        —(CHR¹³)_(o)SO₂R¹⁵; —(CHR¹³)_(o)NR¹SO₂R¹⁵;        —(CHR¹³)_(o)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(o)R²³; or        —(CHR¹)_(n)O(CHR²)_(m)R²³; or-   R⁴ and R²; or R⁵ and R⁶ taken together can form:    -   ═O; ═NR¹; ═NOR¹; ═NOCF₃; or —(CHR¹)_(p)—;-   R⁴ and R⁵; R⁶ and R⁷; R⁷ and R⁸; or R⁶ and R⁹ taken together can    form:    -   —(CHR¹)_(p)—; —(CH₂)_(o)O(CH₂)_(m)—; —(CH₂)_(n)S(CH₂)_(m)—; or        —(CH₂)_(n)NR¹(CH₂)_(m)—;-   R⁹ is H; F; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;    heteroaryl-C₁₋₆-alkyl; —(CHR¹³)_(r)OR¹⁵; —O(CO)R¹⁵;    —(CHR¹³)_(r)SR¹⁵; —(CHR¹⁰)_(r)NR¹⁵R¹⁶; —(CHR¹³)_(r)OCONR¹⁵R¹⁶;    —(CHR¹³)_(r)NR¹CONR¹⁵R¹⁶; —(CHR¹³)_(r)NR¹COR¹⁵; —(CHR¹³)_(o)COOR¹⁵;    —(CHR¹³)_(o)CONR¹⁵R¹⁶; —(CHR¹³)_(r)PO(OR¹)₂; —(CHR¹³)_(r)SO₂R¹⁵;    —(CHR¹³)_(r)NR¹SO₂R¹⁵; —(CHR¹³)_(r)SO₂NR¹⁵R¹⁶; —(CR¹R¹³)_(o)R²³; or    —(CHR¹)_(r)O(CHR¹)_(o)R²³;-   R¹⁰, R¹¹ and R¹² are independently    -   H; F; Cl; Br; I; CF₃; OCF₃; OCHF₂; CN; NO₂; C₁₋₈-alkyl;        C₂₋₈-alkenyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;        heteroaryl-C₁₋₆-alkyl; —(CHR¹³)_(o)OR¹⁵; —O(CO)R¹⁵;        —(CHR¹³)_(o)SR¹⁵; —(CHR¹³)_(o)NR¹⁵R¹⁶; —(CHR¹³)_(o)OCONR¹⁵R¹⁶;        —(CHR¹³)_(o)NR¹CONR¹⁵R¹⁶; —(CHR¹³)_(o)NR¹COR¹⁵;        —(CHR¹³)_(o)COOR¹⁵; —(CHR¹³)_(o)CONR¹⁵R¹⁶; —(CHR¹³)_(o)PO(OR¹)₂;        —(CHR¹³)_(o)SO₂R¹⁵; —(CHR¹³)_(o)NR¹SO₂R¹⁵;        —(CHR¹³)_(o)SO₂NR¹⁵R¹⁶; or —(CR¹R¹³)_(o)R²³;-   R¹³ is H; F; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl; cycloalkyl-C₁₋₆-alkyl;    heterocycloalkyl-C₁₋₆-alkyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;    heteroaryl-C₁₋₆-alkyl; —(CHR¹)_(o)OR¹⁵; —OCOR¹; —(CHR¹)_(o)NR¹⁵R¹⁶;    —COOR¹⁵; —CONR¹⁵R¹⁶; —SO₂R¹⁵; or —SO₂NR¹⁵R¹⁶;-   R¹⁴ is H; CF₃; C₁₋₈-alkyl; C₂₋₈-alkenyl; cycloalkyl;    heterocycloalkyl; cycloalkyl-C₁₋₆-alkyl;    heterocycloalkyl-C₁₋₆-alkyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;    heteroaryl-C₁₋₆-alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl;    cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl;    aryl-heterocycloalkyl; heteroaryl-cycloalkyl;    heteroaryl-heterocycloalkyl; —(CHR¹)_(o)OR¹⁵; —(CHR¹)_(o)SR¹⁵;    —(CHR¹)_(o)NR¹⁵R¹⁶; —(CHR¹)_(o)COOR¹⁵; —(CHR¹)_(o)CONR¹⁵R¹⁶; or    —(CHR¹)_(o)SO₂R¹⁵;-   R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are independently    -   H; C₁₋₈-alkyl; C₂₋₈-alkenyl; C₁₋₆-alkoxy; cycloalkyl;        heterocycloalkyl; cycloalkyl-C₁₋₆-alkyl;        heterocycloalkyl-C₁₋₆-alkyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;        heteroaryl-C₁₋₆-alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl;        cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl;        aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl;        or heteroaryl-heterocycloalkyl; or-   the structural elements —NR¹⁵R¹⁶ and —NR¹⁷R¹⁸ can independently    form:    -   heterocycloalkyl; aryl-heterocycloalkyl; or        heteroaryl-heterocycloalkyl;-   R¹⁹ is an aryl group of one of the formulae

-   -   or a group of one of the formulae

-   X, X′, X″ and X′″ are independently    -   —CR²⁰; or N;-   R²⁰ and R²¹ are independently    -   H; F; Cl; Br; I; OH; NH₂; NO₂; CN; CF₃; OCHF₂; OCF₃; C₁₋₈-alkyl;        C₂₋₈-alkenyl; aryl; heteroaryl; aryl-C₁₋₆-alkyl;        heteroaryl-C₁₋₆-alkyl; —(CH₂)_(o)R²²; —(CH₂)_(o)OR¹⁵; —O(CO)R¹⁵;        —O(CH₂)_(o)R²²; —(CH₂)_(o)SR¹⁵; —(CH₂)_(o)NR¹⁵R¹⁶;        —(CH₂)_(o)OCONR¹⁵R¹⁶; —(CH₂)_(o)NR¹CONR¹⁵R¹⁶;        —(CH₂)_(o)NR¹COR¹⁵; —(CH₂)_(o)COOR¹⁵; —(CH₂)_(o)CONR¹⁵R¹⁶;        —(CH₂)_(o)PO(OR¹)₂; —(CH₂)_(o)SO₂R¹⁴; or —(CH₂)_(o)COR¹⁵;-   R²² is an aryl group of the formula

-   R²³, R²⁴ and R²⁵ are independently    -   H; F; Cl; Br; I; OH; NH₂; NO₂; CN; CF₃; OCHF₂; OCF₃; C₁₋₈-alkyl;        C₂₋₈-alkenyl; —(CH₂)_(o)OR¹⁵; —O(CO)R¹⁵; —(CH₂)_(o)NR¹R¹⁵;        —(CH₂)_(o)COOR¹⁵; —(CH₂)_(o)CONR¹R¹⁵;-   R²⁶ is H; Ac; C₁₋₈-alkyl; or aryl-C₁₋₆-alkyl;-   n and m are independently an integer of 0-5 with the proviso that    n+m≤6;-   o is 0-4; p is 2-6; q is 1-6; and r is 1-3;    or a pharmaceutically acceptable salt thereof.

Each single group “R^(x)” with the same index-number x for x=1-26 isindependently selected on each occurrence in a specific formula and,therefore, they can be the same or different.

As used in this description, the term “alkyl”, taken alone or incombinations (i.e. as part of another group, such as “aryl-C₁₋₆-alkyl”)designates saturated, straight-chain or branched hydrocarbon radicalsand may be optionally substituted. The term “C_(x-y)-alkyl” (x and yeach being an integer) refers to an alkyl group as defined beforecontaining x to y carbon atoms. For example a C₁₋₆-alkyl group containsone to six carbon atoms. Representative examples of alkyl groups includemethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl and the like.

The term “alkenyl”, taken alone or in combinations, designates straightchain or branched hydrocarbon radicals containing at least one or,depending on the chain length, up to four olefinic double bonds. Suchalkenyl moieties are optionally substituted and can independently existas E or Z configurations per double bond, which are all part of theinvention. The term “C_(x-y)-alkenyl” (x and y each being an integer)refers to an alkenyl group as defined before containing x to y carbonatoms.

The term “cycloalkyl”, taken alone or in combinations, refers to asaturated or partially unsaturated alicyclic moiety having from three toten carbon atoms and may be optionally substituted. Examples of thismoiety include, but are not limited to, cyclohexyl, norbornyl, decalinyland the like.

The term “heterocycloalkyl”, taken alone or in combinations, describes asaturated or partially unsaturated mono- or bicyclic moiety having fromthree to nine ring carbon atoms and one or more ring heteroatomsselected from nitrogen, oxygen or sulphur. This term includes, forexample, morpholino, piperazino, azetidinyl, pyrrolidinyl,tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl,1,7-diazaspiro[4.4]nonanyl and the like. Said heterocycloalkyl ring(s)might be optionally substituted.

The term “aryl”, taken alone or in combinations, designates aromaticcarbocyclic hydrocarbon radicals containing one or two six-memberedrings, such as phenyl or naphthyl, which may be optionally substitutedby up to three substituents such as Br, F, CF₃, OH, OCF₃, OCHF₂, NH₂,N(CH₃)₂, NO₂, CN, C₁₋₆-alkyl, C₂₋₆-alkenyl, phenyl or phenoxy.

The term “heteroaryl”, taken alone or in combinations, designatesaromatic heterocyclic radicals containing one or two five- and/orsix-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and wherebythe heteroaryl radicals or tautomeric forms thereof may be attached viaany suitable atom. Said heteroaryl ring(s) are optionally substituted,e.g. as indicated above for “aryl”.

The term “aryl-C_(x-y)-alkyl”, as used herein, refers to anC_(x-y)-alkyl group as defined above, substituted by an aryl group, asdefined above. Representative examples of aryl-C_(x-y)-alkyl moietiesinclude, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl and the like.

The term “heteroaryl-C_(x-y)-alkyl”, as used herein, refers to anC_(x-y)-alkyl group as defined above, substituted by a heteroaryl group,as defined above. Examples of heteroaryl-C_(x-y)-alkyl groups includepyridin-3-ylmethyl, (1H-pyrrol-2-yl)ethyl and the like.

The term “aryl-cycloalkyl”, as used herein, refers to a cycloalkyl groupas defined above, substituted or annelated by an aryl group, as definedabove. Examples of aryl-cycloalkyl moieties include, but are not limitedto, phenylcyclopentyl, 2,3-dihydro-1H-indenyl,1,2,3,4-tetrahydronaphthalenyl and the like.

The term “aryl-heterocycloalkyl”, as used herein, refers to aheterocycloalkyl group as defined above, substituted or annelated by anaryl group, as defined above. Examples of aryl-heterocycloalkyl moietiesinclude, but are not limited to, indolinyl, 1,2,3,4-tetrahydroquinolinyland the like.

The term “heteroaryl-cycloalkyl”, as used herein, refers to a cycloalkylgroup as defined above, substituted or annelated by a heteroaryl group,as defined above. Examples of heteroaryl-cycloalkyl moieties include,but are not limited to, 5,6,7,8-tetrahydroquinolinyl and the like.

The term “heteroaryl-heterocycloalkyl”, as used herein, refers to aheterocycloalkyl group as defined above, substituted or annelated by aheteroaryl group, as defined above. Examples ofheteroaryl-heterocycloalkyl moieties include, but are not limited to,4-(thiazol-2-yl)piperazinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl andthe like.

The terms “cycloalkyl-aryl”, “heterocycloalkyl-aryl”,“cycloalkyl-heteroaryl”, and “heterocycloalkyl-heteroaryl”, as usedherein, are defined analogously to the terms “aryl-cycloalkyl”,“aryl-heterocycloalkyl”, “heteroaryl-cycloalkyl” and“heteroaryl-heterocycloalkyl”, as defined above, but connected in theopposite direction, e.g. instead of 4-(thiazol-2-yl)piperazinyl the termrefers to 2-(piperazin-1-yl)thiazolyl and the like.

The terms “hydroxy”, “alkoxy” and “aryloxy”, taken alone or incombinations, refer to the groups of —OH, —O-alkyl and —O-arylrespectively, wherein an alkyl group or an aryl group is as definedabove. The term “C_(x-y)-alkoxy” (x and y each being an integer) refersto an —O-alkyl group as defined before containing x to y carbon atomsattached to an oxygen atom. Representative examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxyand the like. Examples of aryloxy include e.g. phenoxy. For avoidance ofdoubt e.g. the term “hydroxy-C₁₋₈-alkyl” represents, among others,groups like e.g. hydroxymethyl, 1-hydroxypropyl, 2-hydroxypropyl or3-hydroxy-2,3-dimethylbutyl.

The term “optionally substituted” is in general intended to mean that agroup, such as, is but not limited to C_(x-y)-alkyl, C_(x-y)-alkenyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C_(x-y)-alkoxy andaryloxy may be substituted with one or more substituents independentlyselected from amino (—NH₂), dimethylamino, nitro (—NO₂), halogen (F, Cl,Br, I), CF₃, cyano (—CN), hydroxy, methoxy, ethoxy, phenyloxy,benzyloxy, acetoxy, oxo (═O), carboxy, carboxamido, methyl, ethyl,phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate.

In the context of this invention the term “naturally or non-naturallyoccurring α-amino acid” typically comprises any natural α-amino acid,such as the proteogenic amino acids (examples listed below), theirnatural or semi-synthetic derivatives as well as α-amino acids of purelysynthetic origin. This term includes as well α-amino acids which areoptionally substituted at the α-nitrogen of the amino acid such as, butnot limited to, acetylation or alkylation, e.g. methylation, orbenzylation.

The term “aliphatic α-amino acid” refers to α-amino acids with analiphatic side-chain, such as, but not limited to, alanine, valine,leucine, isoleucine, n-octylglycine etc.

The term “aromatic α-amino acid” refer to α-amino acids with aside-chain comprising an aromatic or heteroaromatic group, such as, butnot limited to, phenylalanine, tryptophan, histidine, O-methyl-tyrosine,4-trifluormethyl-phenylalanine, 3,4-dichloro-homophenylalanine etc.

The term “basic α-amino acid” refers to α-amino acids with a side-chaincomprising at least one amino group, such as, but not limited to,lysine, ornithine etc. and further substituted derivatives thereof. Theaforesaid amino group can be substituted by amidino groups to formα-amino acids, such as, but not limited to, arginine, homoarginine etc.and further substituted derivatives thereof, or by diamino methylidinegroups.

The term “alcoholic α-amino acid” refers to α-amino acids with aside-chain comprising an alcoholic or thioalcoholic group, i.e. ahydroxy or sulfhydryl function, such as, but not limited to, serine,threonine etc.

For the avoidance of doubt the term “single side-chain” in the contextof an α-amino acid refers to a structure where the α-carbon of the aminoacid is covalently connected to the (in-chain) groups of the carbonyl(C═O) and nitrogen (N) as well as to one hydrogen (H) and one variableside-chain, e.g. as defined above. A “single side-chain” may include aswell a heterocyclic structure comprising the α-amino atom, such as butnot limited to, proline, pipecolic acid etc.

For the avoidance of doubt the term “heteroatom” refers to any atom thatis not carbon or hydrogen.

The descriptors L respectively D refer to the stereochemistry at theα-position of an α-amino acid and are used according theFischer-Rosanoff convention of the IUPAC. The peptidomimetics of thepresent invention can also be diastereomers (e.g. epimers) of compoundsof formula (I) if no specific stereochemistry of the chiral center isdetermined in the description. These stereoisomers can be prepared by amodification of the process described below in which the appropriateisomers (e.g. epimers/enantiomers) of chiral starting materials areused. In case of ambiguous stereochemistry in the above description eachsingle epimer is part of the present invention as well as a mixture ofboth.

A further embodiment of the present invention may also includecompounds, which are identical to the compounds of formula (I), exceptthat one or more atoms are replaced by an atom having an atomic massnumber or mass different from the atomic mass number or mass usuallyfound in nature, e.g. compounds enriched in ²H (D), ³H, ¹¹C, ¹⁴C, ¹²⁷Ietc. These isotopic analogs and their pharmaceutical salts andformulations are considered useful agents in the therapy and/ordiagnostic, for example, but not limited to, where a fine-tuning of invivo half-life time could lead to an optimized dosage regimen.

A further particular embodiment of the invention relates to derivativesof general formula (I), wherein specifically

-   T¹ is the D α-amino acid residue AA1^(D); and-   T² is the L α-amino acid residue AA1;    or a pharmaceutically acceptable salt thereof.

An alternative particular embodiment of the invention relates toderivatives of general formula (I), wherein specifically

-   P¹¹ is an L α-amino acid residue of one of the formulae    -   AA7; AA9; or AA11;        or a pharmaceutically acceptable salt thereof.

Another alternative particular embodiment of the invention relates toderivatives of general formula (I), wherein specifically

-   P⁴ is the L α-amino acid residue AA10;-   P⁶ is an α-amino acid residue of one of the formulae    -   AA10^(D); or AA10^(C); and-   P¹⁰ is the L α-amino acid residue AA7;    or a pharmaceutically acceptable salt thereof.

In a further particular embodiment of the invention the elements ofgeneral formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Pro((3R)OH); ^(D)Pro((3S)OH); ^(D)Pro((4R)OH);    ^(D)Pro((4S)OH); ^(D)Pic; or ^(D)Tic;-   T² is Pro; Pro((4R)NH₂); Pro((4S)NH₂); Pro((4R)OH); Pro((4S)OH);    Pro((3R)OH); Pro((3S)OH); Pro((4S)OBn); Pic; Oic; Tic; or Tic(7OH);-   P¹, P³ and P¹⁰ are independently    -   Ala; Abu; Ala(CF₃); Leu; Nle; Ile; Val; Nva; Cha; Chg; tBuGly;        OctGly; Phe; Trp; Tyr; Tyr(Me); or Tza;-   P² and P⁸ are independently    -   His; Phe; Trp; Tyr; Tyr(Me); or Tza;-   P⁴ and P⁹ are independently    -   Ser; Hse; Thr; Dab; Dab(iPr); Dap; Lys; Orn; or Orn(iPr);-   P⁵ and P⁷ are independently    -   Dab; Dab(2PyrMe); Dap; Lys; Orn; or Orn(iPr);-   P⁶ is Dab; Dap; ^(D)Dab; ^(D)Dap; or Pip;-   P¹¹ is Ala; Abu; Ala(CF₃); Leu; Nle; Ile; Val; Nva; Cha; Chg;    tBuGly; OctGly; Alb; Ser; Hse; Asn; Thr; or Tyr; and-   P¹² is Ala; Leu; Ile; Val; Nva; Ser; Hse; Thr; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro; ^(D)Pro((3R)OH); ^(D)Pro((3S)OH); ^(D)Pro((4R)OH);    ^(D)Pro((4S)OH); ^(D)Pic; or ^(D)Tic;-   T² is Pro; Pro((4R)NH₂); Pro((4S)NH₂); Pro((4R)OH); Pro((4S)OH);    Pro((3R)OH); Pro((3S)OH); Pro((4S)OBn); Pic; Oic; Tic; or Tic(7OH);-   P¹, P³ and P¹⁰ are independently    -   Ala; Abu; Ala(CF₃); Leu; Nle; Ile; Val; Nva; Cha; Chg; tBuGly;        OctGly; Phe; Trp; Tyr; Tyr(Me); or Tza;-   P² and P⁸ are independently    -   His; Phe; Trp; Tyr; Tyr(Me); or Tza;-   P⁴ and P⁹ are independently    -   Ser; Hse; Thr; Dab; Dab(iPr); Dap; Lys; Orn; or Orn(iPr);-   P⁵ and P⁷ are independently    -   Dab; Dab(2PyrMe); Dap; Lys; Orn; or Orn(iPr);-   P⁶ is Dab; Dap; ^(D)Dab; ^(D)Dap or Pip;-   P¹¹ is Ala; Abu; Ala(CF₃); Leu; Nle; Ile; Val; Nva; Cha; Chg;    tBuGly; OctGly; Alb; Ser; Hse; Asn; or Thr; and-   P¹² is Ala; Leu; Ile; Val; Nva; Ser; Hse; Thr; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Ile; Val; Nva; or Trp;-   P² is His; Trp; or Tyr;-   P³ is Leu; Cha; tBuGly; Trp; Tyr; or Tyr(Me);-   P⁴ is Dab;-   P⁵ is Orn; or Lys;-   P⁶ is Dab; ^(D)Dab; or Pip;-   P⁷ is Dab;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is tBuGly; Ile; Val; Nva; Cha; Chg; or Trp;-   P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Ile; Val; Nva; or Trp;-   P² is His; Trp; or Tyr;-   P³ is Leu; Cha; tBuGly; Trp; Tyr; or Tyr(Me);-   P⁴ is Dab;-   P⁵ is Orn; or Lys;-   P⁶ is Dab; ^(D)Dab; or Pip;-   P⁷ is Dab;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is tBuGly; Ile; Val; Nva; Cha; Chg; or Trp;-   P¹¹ is Ala; Val; Alb; Ser; or Asn; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Val; Nva; or Trp;-   P² is His; or Trp;-   P³ is Leu; Cha; tBuGly; Tyr; or Tyr(Me);-   P⁴ is Dab;-   P⁵ is Orn; or Lys;-   P⁶ is ^(D)Dab; or Pip;-   P⁷ is Dab;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is tBuGly; Val; Nva; Cha; or Chg;-   P¹¹ is Ala; Val; Alb; or Ser; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; Pro((4S)OH); Pro((3R)OH); or Pro((3S)OH);-   P¹ is Ala; Leu; Ile; Val; Nva; Phe; Trp; or Tyr;-   P² is His; Phe; Trp; or Tyr;-   P³ is Ala; Leu; Ile; Val; Nva; Cha; Chg; tBuGly; Phe; Trp; Tyr; or    Tyr(Me);-   P⁴ and P⁷ are Dab;-   P⁵ is Lys; Orn; or Orn(iPr);-   P⁶ is Dab; Dap; ^(D)Dab; ^(D)Dap or Pip;-   P⁸ is Phe; Trp; Tyr; or Tyr(Me);-   P⁹ is Ser; Hse; Dab; or Dap;-   P¹⁰ is Ala; Leu; Ile; Val; Nva; Cha; Chg; or tBuGly;-   P¹¹ is Ala; Leu; Ile; Val; Nva; Alb; Ser; Hse; or Thr; and-   P¹² is Ala; Leu; Ile; Val; Nva; Ser; Hse; Thr; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Ile; Val; Nva; or Trp;-   P² is His; Trp; or Tyr;-   P³ is Leu; Cha; tBuGly; Trp; Tyr; or Tyr(Me);-   P⁴ and P⁷ are Dab;-   P⁵ is Orn; or Lys;-   P⁶ is ^(D)Dab; or Pip;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is tBuGly; Ile; Val; Nva; Cha; or Chg;-   P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Ile; Val; Nva; or Trp;-   P² is His; Trp; or Tyr;-   P³ is Leu; Cha; tBuGly; Trp; Tyr; or Tyr(Me);-   P⁴ and P⁷ are Dab;-   P⁵ is Orn; or Lys;-   P⁶ is ^(D)Dab; or Pip;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is tBuGly; Ile; Val; Nva; Cha; or Chg;-   P¹¹ is Ala; Val; Alb; Ser; or Asn; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

In another further particular embodiment of the invention the elementsof general formula (I) are defined as follows

-   T¹ is ^(D)Pro;-   T² is Pro; or Pro((3S)OH);-   P¹ is Leu; Val; Nva; or Trp;-   P² is His; or Trp;-   P³ is Leu; Cha; Chg; tBuGly; Tyr; or Tyr(Me);-   P⁴ and P⁷ are Dab;-   P⁵ is Lys; or Orn;-   P⁶ is ° Dab; or Pip;-   P⁸ is Trp;-   P⁹ is Hse; or Dab;-   P¹⁰ is Val; Nva; Cha; Chg; or tBuGly;-   P¹¹ is Ala; Val; Alb; or Ser; and-   P¹² is Val; Ser; or alloThr;    or a pharmaceutically acceptable salt thereof.

Hereinafter follows a list of abbreviations, corresponding to generallyadopted usual practice, of amino acids which, or the residues of which,are suitable for the purposes of the present invention and referred toin this document.

In spite of this specific determination of amino acids, it is notedthat, for a person skilled in the art, it is obvious that derivatives ofthese amino acids, resembling alike structural and physico-chemicalproperties, lead to functional analogs with similar biological activity,and therefore still form part of the gist of this invention.

-   Ala L-Alanine-   Arg L-Arginine-   Asn L-Asparagine-   Asp L-Aspartic acid-   Cit L-Citrulline-   Cys L-Cysteine-   Gln L-Glutamine-   Glu L-Glutamic acid-   Gly Glycine-   His L-Histidine-   Ile L-Isoleucine-   Leu L-Leucine-   Lys L-Lysine-   Met L-Methionine-   Orn L-Ornithine-   Phe L-Phenylalanine-   Pro L-Proline-   Ser L-Serine-   Thr L-Threonine-   Trp L-Tryptophan-   Tyr L-Tyrosine-   Val L-Valine-   Abu (S)-2-aminobutanoic acid-   Agp (S)-2-amino-3-guanidinopropanoic acid-   Ala(tBu) (S)-2-amino-4,4-dimethylpentanoic acid-   Ala(4butoxyPhUr) (S)-2-amino-3-(3-(4-butoxyphenyl)ureido)propanoic    acid-   Ala(cHex) (S)-2-amino-3-cyclohexylpropanoic acid-   Ala(cPr) (S)-2-amino-3-cyclopropylpropanoic acid-   Ala(iPrUr) (S)-2-amino-3-(3-isopropylureido)propanoic acid-   Ala(2ClPhUr) (S)-2-amino-3-(3-(2-chlorophenyl)ureido)propanoic acid-   Ala(4ClPhUr) (S)-2-amino-3-(3-(4-chlorophenyl)ureido)propanoic acid-   Ala(2Furyl) (S)-2-amino-3-(furan-2-yl)propanoic acid-   Ala(3Furyl) (S)-2-amino-3-(furan-3-yl)propanoic acid-   Ala(1Im) (S)-2-amino-3-(1H-imidazol-1-yl)propanoic acid-   Ala(2Im) (S)-2-amino-3-(1H-imidazol-2-yl)propanoic acid-   Ala(Ppz) (S)-2-amino-3-(piperazin-1-yl)propanoic acid-   Ala(cPr) (S)-2-amino-3-cyclopropylpropanoic acid-   Ala(Pyrazinyl) (S)-2-amino-3-(pyrazin-2-yl)propanoic acid-   Ala(1Pyrazolyl) (S)-2-amino-3-(1H-pyrazol-1-yl)propanoic acid-   Ala(3Pyrazolyl) (S)-2-amino-3-(1H-pyrazol-3-yl)propanoic acid-   Ala(2Pyrimidin) (S)-2-amino-3-(pyrimidin-2-yl)propanoic acid-   Ala(4Pyrimidin) (S)-2-amino-3-(pyrimidin-4-yl)propanoic acid-   Ala(5Pyrimidin) (S)-2-amino-3-(pyrimidin-5-yl)propanoic acid-   Ala(3PyrMeUr) (S)-2-amino-3-(3-(pyridin-3-ylmethyl)ureido)propanoic    acid-   Ala(2Quin) (S)-2-amino-3-(quinolin-2-yl)propanoic acid-   Ala(3Quin) (S)-2-amino-3-(quinolin-3-yl)propanoic acid-   Ala(4Quin) (S)-2-amino-3-(quinolin-4-yl)propanoic acid-   Alb (S)-2-amino-3-ureidopropanoic acid-   tBuGly (S)-2-amino-3,3-dimethylbutanoic acid-   Bbta (S)-2-amino-3-(1-benzothiophen-3-yl)propanoic acid-   Bip (S)-2-amino-3-(4-biphenylyl)propanoic acid-   Cha (S)-2-amino-3-cyclohexylpropanoic acid-   Chg (S)-2-amino-2-cyclohexylacetic acid-   Dab (S)-2,4-diaminobutanoic acid-   Dab(Ac) (S)-4-acetamido-2-aminobutanoic acid-   Dab(cPr) (S)-2-amino-4-(cyclopropylamino)butanoic acid-   Dab(iPr) (S)-2-amino-4-(isopropylamino)butanoic acid-   Dab(2PyrMe) (S)-2-amino-4-(pyridin-2-ylmethylamino)butanoic acid-   Dap (S)-2,3-diaminopropanoic acid-   Dap(Ac) (S)-3-acetamido-2-aminopropanoic acid-   Dap(AcThr)    (S)-3-((2S,3R)-2-acetamido-3-hydroxybutanamido)-2-aminopropanoic    acid-   Dap(cPr) (S)-2-amino-3-(cyclopropylamino)propanoic acid-   Dap(iPr) (S)-2-amino-3-(isopropylamino)propanoic acid-   Dap(MeSO₂) (S)-2-amino-3-(methylsulfonamido)propanoic acid-   Dap(2,3-OHpropionyl)    (2S)-2-amino-3-(2,3-dihydroxypropanamido)propanoic acid-   Dap(Thr)    (S)-2-amino-3-((2S,3R)-2-amino-3-hydroxybutanamido)-propanoic acid-   Gly(cPr) (S)-2-amino-2-cyclopropylacetic acid-   hAla(1Im) (S)-2-amino-3-(1H-imidazol-1-yl)-butanoic acid-   hAla(2Im) (S)-2-amino-3-(1H-imidazol-2-yl)-butanoic acid-   hArg (S)-2-amino-6-guanidinohexanoic acid-   hCha (S)-2-amino-4-cyclohexylbutanoic acid-   hCys (S)-2-amino-4-mercaptobutanoic acid-   hHis (S)-2-amino-4-(1H-imidazol-5-yl)butanoic acid-   hLeu (S)-2-amino-5-methylhexanoic acid-   hLys (S)-2,7-diaminoheptanoic acid-   h2Pal (S)-2-amino-4-(pyridin-2-yl)-butanoic acid-   h3Pal (S)-2-amino-4-(pyridine-3-yl)-butanoic acid-   h4Pal (S)-2-amino-4-(pyridine-4-yl)-butanoic acid-   hSer (S)-2-amino-4-hydroxybutanoic acid-   hTrp (S)-2-amino-4-(1H-indol-3-yl)butanoic acid-   hTyr (S)-2-amino-4-(4-hydroxyphenyl)butanoic acid-   His(Me) (S)-2-amino-3-(1-methyl-1H-imidazol-5-yl)propanoic acid-   His(Bn) (S)-2-amino-3-(1-benzyl-1H-imidazol-5-yl)propanoic acid-   Hse (S)-2-amino-4-hydroxybutanoic acid-   Lys(Bz) (S)-2-amino-6-benzamidohexanoic acid-   Lys(Me) (S)-2-amino-6-(methylamino)hexanoic acid-   Lys(Nic) (S)-2-amino-6-(nicotinamido)hexanoic acid-   Met(O₂) (S)-2-amino-4-(methylsulfonyl)butanoic acid-   1Nal (S)-2-amino-3-naphthalen-1-ylpropanoic acid-   2Nal (S)-2-amino-3-naphthalen-2-ylpropanoic acid-   Nle (S)-2-amino-hexanoic acid-   Nle(6OBn) (S)-2-amino-6-(benzyloxy)hexanoic acid-   Nva (S)-2-aminopentanoic acid-   OctG (S)-2-aminodecanoic acid-   Oic (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid-   Orn(Ac) (S)-5-acetamido-2-aminopentanoic acid-   Orn(cPr) (S)-2-amino-5-(cyclopropylamino)pentanoic acid-   Orn(iPr) (S)-2-amino-5-(isopropylamino)pentanoic acid-   2Pal (S)-2-amino-3-(pyridine-2-yl) propionic acid-   3Pal (S)-2-amino-3-(pyridine-3-yl)propionic acid-   4Pal (S)-2-amino-3-(pyridine-4-yl)propionic acid-   Phe(2Cl) (S)-2-amino-3-(2-chlorophenyl)propanoic acid-   Phe(3Cl) (S)-2-amino-3-(3-chlorophenyl)propanoic acid-   Phe(4Cl) (S)-2-amino-3-(4-chlorophenyl)propanoic acid-   Phe(3,4Cl₂) (S)-2-amino-3-(3,4-dichlorophenyl)propanoic acid-   Phe(2F) (S)-2-amino-3-(2-fluorophenyl)propanoic acid-   Phe(3F) (S)-2-amino-3-(3-fluorophenyl)propanoic acid-   Phe(4F) (S)-2-amino-3-(4-fluorophenyl)propanoic acid-   Phe(3,4F₂) (S)-2-amino-3-(3,4-difluorophenyl)propanoic acid-   Phe(3CN) (S)-2-amino-3-(3-cyanophenyl)propanoic acid-   Phe(4CN) (S)-2-amino-3-(4-cyanophenyl)propanoic acid-   Phe(2CF₃) (S)-2-amino-3-(2-(trifluoromethyl)phenyl)propanoic acid-   Phe(3CF₃) (S)-2-amino-3-(3-(trifluoromethyl)phenyl)propanoic acid-   Phe(4CF₃) (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoic acid-   Phe(3,4(CF₃)₂)    (S)-2-amino-3-(3,4-bis(trifluoromethyl)phenyl)propanoic acid-   Phe(4COOMe) (S)-2-amino-3-(4-(methoxycarbonyl)phenyl)propanoic acid-   Phg (S)-2-amino-2-phenylacetic acid-   Pic (S)-piperidine-2-carboxylic acid-   Pip 4-aminopiperidine-4-carboxylic acid-   Pro((4R)NH₂) (2S,4R)-4-aminopyrrolidine-2-carboxylic acid-   Pro((4S)NH₂) (2S,4S)-4-aminopyrrolidine-2-carboxylic acid-   Pro((3R)OH) (2S,3R)-3-hydroxypyrrolidine-2-carboxylic acid-   Pro((3S)OH) (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid-   Pro((4R)OH) (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid-   Pro((4S)OH) (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid-   Pro((4R)OBn) (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid-   Pro((4S)OBn) (2S,4S)-4-(benzyloxy)pyrrolidine-2-carboxylic acid-   Ser(Bn) (S)-2-amino-3-(benzyloxy)propanoic acid-   Ser(Me) (S)-2-amino-3-methoxy-propanoic acid-   Thi (S)-2-amino-3-(thiophen-2-yl)propanoic acid-   alloThr (2S,3S)-2-amino-3-hydroxybutanoic acid-   Thr(Bn) (2S,3R)-2-amino-3-(benzyloxy)butanoic acid-   Thr(Me) (2S,3R)-2-amino-3-(methyloxy)butanoic acid-   Thz (R)-thiazolidine-4-carboxylic acid-   Thz(5,5Me₂) (R)-2,2-dimethylthiazolidine-4-carboxylic acid-   Tic (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid-   Tic(70H) (S)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic    acid-   Trp(7Aza) (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic    acid-   Trp(5Br) (S)-2-amino-3-(5-bromo-1H-indol-3-yl)propanoic acid-   Trp(6Br) (S)-2-amino-3-(6-bromo-1H-indol-3-yl)propanoic acid-   Trp(6CF₃) (S)-2-amino-3-(6-(trifluoromethyl)-1H-indol-3-yl)propanoic    acid-   Trp(5Cl) (S)-2-amino-3-(5-chloro-1H-indol-3-yl)propanoic acid-   Trp(6Cl) (S)-2-amino-3-(6-chloro-1H-indol-3-yl)propanoic acid-   Trp(5,6Cl) (S)-2-amino-3-(5,6-dichloro-1H-indol-3-yl)propanoic acid-   Trp(5OH) (S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid-   Tyr(Bn) (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid-   Tyr(Me) (S)-2-amino-3-(4-methoxyphenyl)propanoic acid-   Tyr(Ph) (S)-2-amino-3-(4-phenoxyphenyl)propanoic acid-   Tyr(4OHPh) (S)-2-amino-3-[4-(4-hydroxyphenoxy)phenyl]propanoic acid-   Tza (S)-2-amino-3-(thiazol-4-yl)propanoic acid

The abbreviation of D-isomers, e.g. ^(D)Lys corresponds to the epimer atthe 2-position of the appropriate amino acid described above. Sameapplies for the generic descriptions of the amino acids, e.g. AA1 whichhas AA1^(D) as the corresponding α-epimer.

In preferred embodiment of the invention the 0-hairpin peptidomimeticsof general formula (I) are selected from the group consisting of:

-   -   cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);    -   cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);    -   cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);    -   cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);        or a pharmaceutically acceptable salt thereof.

In another preferred embodiment of the invention the β-hairpinpeptidomimetics of general formula (I) are selected from the groupconsisting of:

-   -   cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);    -   cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);        or a pharmaceutically acceptable salt thereof.

In another preferred embodiment of the invention the β-hairpinpeptidomimetic of general formula (I) is:

-   -   cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);        or a pharmaceutically acceptable salt thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

-   a) coupling an appropriately functionalized solid support with an    appropriately N-protected derivative of that amino acid which in the    desired end-product is in position T¹ or T² or P¹ to P¹² as defined    above; any functional group which may be present in said N-protected    amino acid derivative being likewise appropriately protected;-   (b) removing the N-protecting group from the product obtained in    step (a);-   (c) coupling the product thus obtained with an appropriately    N-protected derivative of that amino acid which in the desired    end-product is in the position of the next element (T or P),    following counterclockwise or clockwise the to sequence according to    general formula (I) in —COOH to —NH2 orientation; any functional    group which may be present in said N-protected amino acid derivative    being likewise appropriately protected;-   (d) removing the N-protecting group from the product thus obtained;-   (e) repeating steps (c) and (d) until all amino acid residues have    been introduced;-   (f) if desired, selectively deprotecting one or several protected    functional group(s) present in the molecule and chemically    transforming the reactive group(s) thus liberated;-   (g) detaching the product thus obtained from the solid support;-   (h) cyclizing the product cleaved from the solid support;-   (i) removing any protecting groups present on functional groups of    any members of the chain of amino acid residues and, if desired, any    protecting group(s) which may in addition be present in the    molecule;-   (j) if desired, implementing additional chemical transformations of    one or more reactive group(s) present in the molecule; and-   (k) if desired, converting the product thus obtained into a    pharmaceutically acceptable salt or converting a pharmaceutically    acceptable, or unacceptable, salt thus obtained into the    corresponding free compound of formula (I) or into a different,    pharmaceutically acceptable salt.

Enantiomers of the compounds defined herein before form also part of thepresent invention. These enantiomers can be prepared by a modificationof the above process wherein enantiomers of all chiral startingmaterials are utilized.

The process of the invention can advantageously be carried out asparallel array synthesis to yield libraries of β-hairpin peptidomimeticsof the invention. Such parallel syntheses allow one to obtain arrays ofnumerous (normally 12 to 192, typically 96) compounds as described abovein moderate to high yields and defined purities, minimizing theformation of dimeric and polymeric by-products. The proper choice of thefunctionalized solid-support (i.e. solid support plus linker molecule)and site of cyclization play thereby key roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel™); andpolyacrylamide resins (see also D. Obrecht, J.-M. Villalgordo,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidicconditions (H. Rink, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl) phenoxyacetamido)aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl]-4-methyl-benzydrylaminePS resin (Rink amide MBHA PS Resin), and 4-[(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] benzhydrylamine PS-resin(Rink amide BHA PS resin). Preferably, the support is derived frompolystyrene crosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 4-(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin™ linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array synthesis the process of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the invention.

A number of reaction vessels (normally 12 to 192, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 60 mg, of the appropriatefunctionalized solid support, preferably 1 to 5% cross-linkedpolystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (G. B. Fields, C. G. Fields, J. Am. Chem. Soc. 1991, 113,4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin™ linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008)is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) andis stable to Fmoc deprotection conditions during the peptide synthesis,Boc/tBu-based additional protecting groups being compatible with thisprotection scheme. Other linkers which are suitable for the process ofthe invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, H.Rink, Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Florsheimer & Riniker, 1991, Peptides 1990: Proceedings ofthe Twenty-First European Peptide Symposium, 131) which is also cleavedwith 1% TFA/DCM in order to yield a peptide fragment containing all acidlabile side-chain protective groups; and, in addition, the2-chlorotritylchloride linker (Barlos et al., Tetrahedron Lett. 1989,30, 3943-3946), which allows the peptide detachment using a mixture ofglacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenylmethyl or trityl

-   -   for the carboxyl group (as is present e.g. also in the        side-chain of aspartic and glutamic acid) by conversion into        esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac phenacyl allyl Tsetrimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e.g. in the side-chain of        arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl;

-   -   and for the hydroxy group (as is present e.g. in the side-chain        of threonine and serine)

tBu tert.-butyl Bn benzyl Trt trityl Alloc allyloxycarbonyl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of theβ-hairpin loop mimetics of the invention. For the deprotection, i.e.cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2%piperidine in DMF can be used as well as 25% hexafluoroisopropanol inCH₂Cl₂.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used, if required, todrive the reaction to completion in a reasonable time. The preferredworkstations (without, however, being limited thereto) are Labsource'sCombi-chem station, Protein Technologies' Symphony and MultiSynTech's-Syro synthesizer, the latter additionally equipped with atransfer unit and a reservoir box during the process of detachment ofthe fully protected linear peptide from the solid support. Allsynthesizers are able to provide a controlled environment, for example,reactions can be accomplished at temperatures different from roomtemperature as well as under inert gas atmosphere, if desired.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and,respectively, diisopropylurea is insoluble and, respectively, soluble inthe solvents generally used. In a variation of the carbodiimide method1-hydroxy benzotriazole (HOBt, König & Geiger, Chem. Ber. 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-(dimethyl-amino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetra methyluronium tetrafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino etal., Tetrahedron Lett. 1994, 35, 2279-2281) or-(6-Chloro-1H-benzotriazol-1-yl-)-N,N,N′,N′-1,1,3,3-tetramethyl uroniumtetrafluoroborate (TCTU), or hexafluoro phosphate (HCTU, Marder, Shivoand Albericio: HCTU and TCTU: New Coupling Reagents: Development andIndustrial Applications, Poster Presentation, Gordon Conference February2002) have also been used as coupling reagents as well as1,1,3,3-bis(tetramethylene)chlorouronium hexafluorophosphate (PyClU)especially for coupling of N-methylated amino acids (J. Coste, E.Frérot, P. Jouin, B. Castro, Tetrahedron Lett. 1991, 32, 1967) orpentafluorophenyl diphenyl-phosphinate (S. Chen, J. Xu, TetrahedronLett. 1991, 32, 6711).

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide or peptide indicates qualitatively the presence ofthe primary amine, can easily and quickly be performed after eachcoupling step. Fmoc chemistry allows the spectrophotometric detection ofthe Fmoc chromophore when it is released with the base (Meienhofer etal., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction vessel is washed freeof excess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s).

Washing procedures are repeated up to about 30 times (preferably about 5times), monitoring the efficiency of reagent, solvent, and by-productremoval by methods such as TLC, GC, LC-MS or inspection of the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such an amino protecting group which can be selectivelyremoved, e.g. by means of Pd^(o) and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced.

After detachment of the fully protected linear peptide from the solidsupport the individual solutions/extracts are then manipulated as neededto isolate the final compounds. Typical manipulations include, but arenot limited to, evaporation, concentration, liquid/liquid extraction,acidification, basification, neutralization or additional reactions insolution.

The solutions containing fully protected linear peptide derivativeswhich have been cleaved off from the solid support and neutralized witha base, are evaporated. Cyclization is then effected in solution usingsolvents such as DCM, DMF, dioxane, THF and the like. Various couplingreagents which were mentioned earlier as activators for the amide bondformation can be used for the cyclization. The duration of thecyclization is about 6-48 hours, preferably about 16 hours. The progressof the reaction is followed, e.g. by RP-HPLC (Reverse Phase HighPerformance Liquid Chromatography). Then the solvent is removed byevaporation, the fully protected cyclic peptide derivative is dissolvedin a solvent which is not miscible with water, such as DCM, and thesolution is extracted with water or a mixture of water-misciblesolvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA,2.5% H₂O, 2.5% TIS, or 87.5% TFA, 2.5% DODT, 5% thioanisol, 5% H₂O oranother combination of scavengers for effecting the cleavage ofprotecting groups. The cleavage reaction time is commonly 30 minutes to12 hours, preferably about 2.5 hours. The volatiles are evaporated todryness and the crude peptide is dissolved in 20% AcOH in water andextracted with isopropyl ether or other solvents which are suitabletherefore. The aqueous layer is collected and evaporated to dryness, andthe fully deprotected cyclic peptide is obtained. Alternatively thedeprotected cyclic peptide can be precipitated and washed using coldEt₂O.

For some compounds of the present invention according general formula(I) additional synthetic steps are required. These transformations canbe applied either on a partially deprotected cyclic or linear peptide,attached or already released from the solid support or on the finaldeprotected molecule.

Depending on its purity, the final product as obtained above can be useddirectly for biological assays, or has to be further purified, forexample by preparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to convertthe fully deprotected cyclic product thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree or into a different, pharmaceutically acceptable, salt. Any ofthese operations can be carried out by methods well known in the art.

In general the building blocks for the peptidomimetics of the presentinvention can be synthesized according to the literature methods, whichare known to a person skilled in the art or are commercially available.All other corresponding amino acids have been described either asunprotected or as Boc- or Fmoc-protected racemates, (D)- or (L)-isomers.It will be appreciated that unprotected amino acid building blocks canbe easily transformed into the corresponding Fmoc-protected amino acidbuilding blocks required for the present invention by standardprotecting group manipulations. Reviews describing general methods forthe synthesis of α-amino acids include: R. Duthaler, Tetrahedron(Report) 1994, 349, 1540-1650; R. M. Williams, “Synthesis of opticallyactive α-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J.E. Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989. Anespecially useful method for the synthesis of optically active α-aminoacids relevant for this invention includes kinetic resolution usinghydrolytic enzymes (M. A. Verhovskaya, I. A. Yamskov, Russian Chem. Rev.1991, 60, 1163-1179; R. M. Williams, “Synthesis of optically activeα-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J. E.Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989, Chapter 7,p. 257-279). Kinetic resolution using hydrolytic enzymes involveshydrolysis of amides and nitriles by aminopeptidases or nitrilases,cleavage of N-acyl groups by acylases, and ester hydrolysis by lipasesor proteases. It is well documented that certain enzymes will leadspecifically to pure (L)-enantiomers whereas others yield thecorresponding (D)-enantiomers (e.g.: R. Duthaler, Tetrahedron Report1994, 349, 1540-1650; R. M. Williams, “Synthesis of optically activeα-amino acids”, Tetrahedron Organic Chemistry Series, Vol. 7, J. E.Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989).

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to inhibit the growth of or to killmicroorganisms leading to the desired therapeutic effect in man or, dueto their similar etiology, in other mammals. In particular they can beused to inhibit the growth of or to kill Gram-negative bacteria such asKlebsiella pneumoniae and/or Acinetobacter baumannii and/or Escherichiacoli.

They can be used for example as disinfectants or as preservatives formaterials such as foodstuffs, cosmetics, medicaments and othernutrient-containing materials. The β-hairpin peptidomimetics of theinvention can also be used to treat or prevent diseases related tomicrobial infection in plants and animals.

For use as disinfectants or preservatives the β-hairpin peptidomimeticscan be added to the desired material singly, as mixtures of severalβ-hairpin peptidomimetics or in combination with other antimicrobialagents.

The β-hairpin peptidomimetics of the invention can be used to treat orprevent infections or diseases related to such infections, particularlynosocomial infections caused by Gram-negative bacteria related todiseases such as ventilator-associated pneumonia (VAP),hospital-acquired pneumonia (HAP), healthcare-associated pneumonia(HCAP); catheter-related and non-catheter-related infections such asurinary tract infections (UTIs) or bloodstream infections (BSIs);infections related to respiratory diseases such as cystic fibrosis,emphysema, asthma or pneumonia; infections related to skin or softtissue diseases such as surgical wounds, traumatic wounds or burn;infections related to gastrointestinal diseases such as epidemicdiarrhea, necrotizing enterocolitis, typhlitis, gastroenteritis orpancreatitis; infections related to eye diseases such as keratitis andendophthalmitis; infections related to ear diseases such as otitis;infections related to CNS diseases such as brain abscess and meningitisor encephalitis; infections related to bone diseases such asosteochondritis and osteomyelitis; infections related to cardiovasculardiseases such as endocartitis and pericarditis; or infections related togenitourinary diseases such as epididymitis, prostatitis and urethritis.They can be administered singly, as mixtures of several β-hairpinpeptidomimetics, in combination with other antimicrobial or antibioticagents, or anti cancer agents, or antiviral (e.g. anti-HIV) agents, orin combination with other pharmaceutically active agents. The β-hairpinpeptidomimetics can be administered per se or as pharmaceuticalcompositions.

The β-hairpin peptidomimetics of the invention may be administered perse or may be applied as an appropriate formulation together withcarriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active β-hairpin peptidomimetics intopreparations which can be used pharmaceutically. Proper formulationdepends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solutions may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the β-hairpin peptidomimetics of the invention may be inpowder form for combination with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion by a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, disintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aerosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described above, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide may also be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent (e.g. for coated stents).Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic agent, additional strategies forprotein stabilization may be employed.

As the β-hairpin peptidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For example, for use as a disinfectant or preservative, anantimicrobially effective amount of a β-hairpin peptidomimetic of theinvention, or a composition thereof, is applied or added to the materialto be disinfected or preserved. By antimicrobially effective amount ismeant an amount of a β-hairpin peptidomimetic of the invention, or acomposition thereof, that inhibits the growth of, or is lethal to, atarget microbe population. While the antimicrobially effective amountwill depend on a particular application, for use as disinfectants orpreservatives the β-hairpin peptidomimetics of the invention, orcompositions thereof, are usually added or applied to the material to bedisinfected or preserved in relatively low amounts. Typically, theβ-hairpin peptidomimetics of the invention comprise less than about 5%by weight of a disinfectant solution or material to be preserved,preferably less than 1% by weight and more preferably less than 0.1% byweight. An ordinary skilled expert will be able to determineantimicrobially effective amounts of particular β-hairpinpeptidomimetics of the invention for particular applications withoutundue experimentation using, for example, the results of the in vitroassays provided in the examples.

For use to treat or prevent microbial infections or diseases related tosuch infections, the β-hairpin peptidomimetics of the invention, orcompositions thereof, are administered or applied in a therapeuticallyeffective amount. By therapeutically effective amount is meant an amounteffective in ameliorating the symptoms of, or in ameliorating, treatingor preventing microbial infections or diseases related thereto.Determination of a therapeutically effective amount is well within thecapacities of those skilled in the art, especially in view of thedetailed disclosure provided herein.

As in the case of disinfectants and preservatives, for topicaladministration to treat or prevent bacterial infections and/or viralinfections a therapeutically effective dose can be determined using, forexample, the results of the in vitro assays provided in the examples.The treatment may be applied while the infection is visible, or evenwhen it is not visible. An ordinary skilled expert will be able todetermine therapeutically effective amounts to treat topical infectionswithout undue experimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skill in the art could readily optimize administration tohumans based on animal data.

Dosage amounts for applications as anti-infective agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the ordinaryskill in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The antimicrobial therapy may be repeated intermittently whileinfections are detectable or even when they are not detectable. Thetherapy may be provided alone or in combination with other drugs, suchas for example anti-HIV agents or anti-cancer agents, or otherantimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the present invention but are not tobe construed as limiting its scope in any way.

Abbreviations

-   -   Ac Acetyl;    -   BSA Bovine serum albumin;    -   Boc Cert-Butyloxycarbonyl;    -   DCHA Dicyclohexylamine;    -   DEAD Diethyl azodicarboxylate;    -   DIPEA Diisopropylethylamine;    -   DMEM Dulbecco's Modified Eagle's Medium;    -   DODT 3,6-dioxa-1,8-octanedithiol;    -   FCS Fetal Calf Serum;    -   Fmoc Fluorenylmethyloxycarbonyl;    -   HATU O-(7-Aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate;    -   HBSS Hank's Buffered Salt Solution;    -   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   HCTU O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   Hepes 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;    -   HOAt 1-Hydroxy-7-azabenzotriazole;    -   IMDM Iscove's Modified Dulbecco's Media;    -   PyBop® (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate;    -   TIS Triisopropylsilane;    -   TPP Triphenylphosphine;    -   RPMI Roswell Park Memorial Institute medium;    -   rt Room temperature.

EXAMPLES

1. Peptide Synthesis

1.1 General Synthetic Procedures

A general method for the synthesis of the peptidomimetics of the presentinvention is exemplified in the following. This is to demonstrate theprincipal concept and does not limit or restrict the present inventionin any way. A person skilled in the art is easily able to modify theseprocedures, especially, but not limited to, choosing a differentstarting position within the ring system, to still achieve thepreparation of the claimed cyclic peptidomimetic compounds of thepresent invention.

Coupling of the First Protected Amino Acid Residue to the Resin

In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1%crosslinked; loading: 1.4 mmol/g) was swollen in dry CH₂Cl₂ for 30 min(7 ml CH₂Cl₂ per g resin), A solution of 0.8 eq of the Fmoc-protectedamino acid and 6 eq of DIPEA in dry CH₂Cl₂/DMF (4/1) (10 ml per g resin)was added. After shaking for 2-4 h at rt the resin was filtered off andwashed successively with CH₂Cl₂, DMF, CH₂Cl₂, DMF and CH₂Cl₂. Then asolution of dry CH₂Cl₂/MeOH/DIPEA (17:2:1) was added (10 ml per gresin). After shaking for 3×30 min the resin was filtered off in apre-weighed sinter funnel and washed successively with CH₂Cl₂, DMF,CH₂Cl₂, MeOH, CH₂Cl₂, MeOH, CH₂Cl₂ (2×) and Et₂O (2×). The resin wasdried under high vacuum overnight. The final mass of resin wascalculated before the qualitative control.

The following preloaded resins were prepared:Fmoc-Dab(Boc)-2-chlorotrityl resin, Fmoc-Pro-2-chlorotrityl resin,Fmoc-^(D)Pro-2-chlorotrityl resin, Fmoc-alloThr-2-chlorotrityl resin,and Fmoc-Tyr(Me)-2-chlorotrityl resin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out on a Syro-peptide synthesizer(MultiSynTech GmbH) using 24 to 96 reaction vessels. In each vessel wereplaced approximately 80 mg of the above resin (weight of the resinbefore loading). The following reaction cycles were programmed andcarried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 1 × 3 min 2 DMF,wash and swell 2 × 30 min  3 20% piperidine/DMF 1 × 5 min and 1 × 15 min4 DMF, wash 5 × 1 min 5 3.5 eq. Fmoc amino acid/ 1 × 60 min  DMF + 3.5eq. PyBOP + 7 eq. DIPEA 6 3.5 eq. Fmoc amino acid/ 1 × 60 min  DMF + 3.5eq. HATU or PyBOP or HCTU + 7 eq. DIPEA 7 DMF, wash 5 × 1 min 8 20%piperidine/DMF 1 × 5 min and 1 × 15 min 9 DMF, wash 5 × 1 min 10 CH₂Cl₂,wash (at the end of 3 × 1 min the synthesis)

Steps 5 to 9 are repeated to add each amino-acid residue.

After the synthesis of the fully protected peptide fragment had beenterminated, the cleavage, cyclization and work up procedures, asdescribed herein below, were used for the preparation of the finalcompounds.

Cleavage, Backbone Cyclization and Deprotection

After assembly of the linear peptide, the resin was suspended in 1 ml of1% TFA in CH₂Cl₂ (v/v; 0.14 mmol) for 3 minutes and filtered, and thefiltrate was neutralized with 1 ml of 20% DIPEA in CH₂Cl₂ (v/v; 1.15mmol). This procedure was repeated four times to ensure completion ofthe cleavage. The resin was washed three times with 1 ml of CH₂Cl₂. TheCH₂Cl₂ layers containing product were evaporated to dryness.

The fully protected linear peptide was solubilised in 8 ml of dry DMF.Then 2 eq. of HATU and 2. eq. of HOAt in dry DMF (1-2 ml) and 4 eq. ofDIPEA in dry DMF (1-2 ml) were added to the peptide, followed bystirring for ca. 16 h. The volatiles were removed by evaporation. Thecrude cyclic peptide was dissolved in 7 ml of CH₂Cl₂ and washed threetimes with 4.5 ml 10% acetonitrile in water (v/v). The CH₂Cl₂ layer wasthen evaporated to dryness.

To fully deprotect the peptide, 7 ml of cleavage cocktailTFA/DODT/thioanisol/H₂O (87.5:2.5:5:5) were added, and the mixture waskept for 2.5-4 h at room temperature until the reaction was completed.The reaction mixture was evaporated close to dryness and the peptideprecipitated with 7 ml of cold Et₂O. The precipitate was washed 3 timeswith 4 ml of cold Et₂O.

Purification Procedure (Preparative Reverse Phase LC-MS)

Compounds were purified by reverse phase chromatography using aPhenomenex Gemini NX-C18 column, 30×100 mm, 5 μm (Cat No.00D-4435-U0-AX) or a Waters XBridge C18 OBD column, 30×100 mm, 5 μm (CatNo. 186002982).

Mobile phases used were:

A: 0.1% TFA in Water/Acetonitrile 95/5 v/v

B: 0.1% TFA in Acetonitrile

Gradient slopes in the preparative runs were adapted each time based onanalytical LC-MS analysis of the crude product. As an example, a typicalrun (purification of Ex. 11) was executed using the Phenomenex columnwith a flow rate of 35 ml/min running a gradient from 0-1 min 0% B, at1.1 min 25% B to a final of 8 min 45% B (retention time: 5.96 min inthis case).

Detection: MS and UV @ 220 nm

Fractions collected were evaporated using a Genevac HT4 evaporator or aBüchi system.

Alternatively for larger amounts the following LC-purification systemwas used:

Column: Waters XBridge C18 OBD column, 50×250 mm, 10 μm (Cat No.186003900)

Mobile phase A: 0.1% TFA in Water

Mobile phase B: Acetonitrile

Flow rate: 150 ml/min

Detection: UV @ 220 nm

After lyophilisation the products were obtained typically as white tooff-white powders and analysed by HPLC-ESI-MS methods as describedbelow. Analytical data after preparative HPLC purification are shown inTable 1.

1.2 Analytical Methods

Analytical Method A:

Analytical HPLC retention times (RT, in minutes) were determined usingan Ascentis Express C18 column, 50×2.1 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B (CH₃CN+0.085% TFA) and the gradient:0-0.05 min: 97% A, 3% B; 3.3 min: 15% A, 85% B; 3.32 min: 3% A, 97% B;3.32-3.55 min: 3% A, 97% B; 3.57-3.7 min: 97% A, 3% B. Flow rate=1.6ml/min at 55° C.

Analytical Method B:

Analytical HPLC retention times (RT, in minutes) were determined usingan Ascentis Express C18 column, 50×3.0 mm, 2.7 μm, with the followingsolvents A (H₂O+0.1% TFA) and B (CH₃CN+0.085% TFA) and the gradient:0-0.05 min: 97% A, 3% B; 4.95 min: 3% A, 97% B; 4.95-5.35 min: 3% A, 97%B; 5.37-5.4 min: 97% A, 3% B. Flow rate=1.3 ml/min at 55° C.

Analytical Method C:

Analytical HPLC retention times (RT, in minutes) were determined usingan Gemini NX C18 column, 50×2.0 mm, 3.0 μm, with the following solventsA (H₂O+0.1% TFA) and B (CH₃CN+0.085% TFA) and the gradient: 0-0.1 min:97% A, 3% B; 2.7 min: 3% A, 97% B; 2.7-3.0 min: 3% A, 97% B; 3.05-3.3min: 97% A, 3% B. Flow rate=0.8 ml/min at 45° C.

1.3 Synthesis of Peptide Sequences

Examples 1-13, 18-38 are shown in Table 1.

The peptides were synthesized according the general method starting withthe amino acid L-prolin, which was grafted to the resin(Fmoc-Pro-2-chlorotrityl resin). The linear peptides were synthesized onthe solid support according to the procedure described above in thefollowing sequence: Resin-Pro-T¹-P¹²—P¹¹—P¹⁰—P⁹—P⁸—P⁷—P⁶—P⁵—P⁴—P³—P²—P¹.The products were cleaved from the resin, cyclized, deprotected, andfinally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the products were obtained as white to off-whitepowders and characterised by HPLC-MS. For analytical data, see Ex. 1-13,18-38 in Table 1.

Example 14 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid D-proline, which was grafted to the resin(Fmoc-^(D)Pro-2-chlorotrityl resin). The linear peptide was synthesizedon the solid support according to the procedure described above in thefollowing sequence:Resin-^(D)Pro-Ser-Ser-tBuGly-Dab-Trp-Dab-Pip-Orn-Dab-Cha-His-Trp-Pro((3S)OH).The product was cleaved from the resin, cyclized, deprotected andfinally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off-whitepowder and characterised by HPLC-MS. For analytical data, see Ex. 14 inTable 1.

Example 15 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid (S)-2-amino-4-(tert-butoxycarbonylamino)butanoic acid,which was grafted to the resin (Fmoc-Dab(Boc)-2-chlorotrityl resin). Thelinear peptide was synthesized on the solid support according to theprocedure described above in the following sequence:Resin-Dab-Cha-Trp-Trp-Pro((3S)OH)-^(D)Pro-Ser-Ser-tBuGly-Dab-Trp-Dab-^(D)Dab-Orn.The product was cleaved from the resin, cyclized, deprotected andfinally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off-whitepowder and characterised by HPLC-MS. For analytical data, see Ex. 15 inTable 1.

Example 16 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid (S)-2-amino-3-(4-methoxyphenyl)propanoic acid, which wasgrafted to the resin (Fmoc-Tyr(Me)-2-chlorotrityl resin). The linearpeptide was synthesized on the solid support according to the proceduredescribed above in the following sequence:Resin-Tyr(Me)-His-Trp-Pro-^(D)Pro-Ser-Ala-tBuGly-Hse-Trp-Dab-^(D)Dab-Orn-Dab.The product was cleaved from the resin, cyclized, deprotected andfinally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off-whitepowder and characterised by HPLC-MS. For analytical data, see Ex. 16 inTable 1.

Example 17 is shown in Table 1.

The peptide was synthesized according the general method starting withthe amino acid (2S,3S)-2-amino-3-hydroxybutanoic acid, which was graftedto the resin (Fmoc-alloThr-2-chlorotrityl resin). The linear peptide wassynthesized on the solid support according to the procedure describedabove in the following sequence:Resin-alloThr-Ala-tBuGly-Dab-Trp-Dab-^(D)Dab-Orn-Dab-Cha-His-Leu-^(D)Pro-Pro.The product was cleaved from the resin, cyclized, deprotected andfinally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off-whitepowder and characterised by HPLC-MS. For analytical data, see Ex. 17 inTable 1.

1.4 Sequence Data

TABLE 1 Examples (Ex.) Ana- Pu- lyt. RT rity Ex. P¹ ^(a)) P² ^(a)) P³^(a)) P⁴ ^(a)) P⁵ ^(a)) P⁶ ^(a)) P⁷ ^(a)) P⁸ ^(a)) P⁹ ^(a)) P¹⁰ ^(a))P¹¹ ^(a)) P¹² ^(a)) T¹ ^(a)) T² ^(a)) Meth. MS^(b)) [min] [%] 1 Trp HisTyr Dab Orn ^(D)Dab Dab Trp Hse tBuGly Ala Ser ^(D)Pro Pro B 827.3 1.8187 2 Trp His Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro ProB 827.0 1.82 88 3 Trp His Cha Dab Orn ^(D)Dab Dab Trp Dab Nva Ala Ser^(D)Pro Pro B 815.2 1.93 93 4 Trp His Cha Dab Orn ^(D)Dab Dab Trp DabtBuGly Val Ser ^(D)Pro Pro A 558.0 1.33 82 5 Leu His Tyr Dab Orn ^(D)DabDab Trp Dab tBuGly Ala Ser ^(D)Pro Pro B 790.5 1.80 87 6 Leu His Cha DabOrn Pip Dab Trp Dab tBuGly Alb Ser ^(D)Pro Pro B 827.4 1.98 85 7 Val HisTyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro Pro B 522.6 1.7395 8 Nva His Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro ProB 783.5 1.72 89 9 Trp His Cha Dab Orn ^(D)Dab Dab Trp Dab Chg Alb Ser^(D)Pro Pro A 576.4 1.33 68 10 Trp Trp Cha Dab Lys ^(D)Dab Dab Trp DabChg Ala Ser ^(D)Pro Pro C 578.1 1.60 94 11 Trp Trp Cha Dab Lys ^(D)DabDab Trp Dab tBuGly Ala Ser ^(D)Pro Pro C 569.4 1.57 99 12 Trp Trp tBuGlyDab Orn ^(D)Dab Dab Trp Dab Cha Ala Ser ^(D)Pro Pro C 847.0 1.57 92 13Trp Trp Leu Dab Orn ^(D)Dab Dab Trp Dab Val Ala Val ^(D)Pro Pro A 550.61.53 88 14 Trp His Cha Dab Orn Pip Dab Trp Dab tBuGly Ser Ser ^(D)ProPro((3S)OH) B 851.0 1.90 90 15 Trp Trp Cha Dab Orn ^(D)Dab Dab Trp DabtBuGly Ser Ser ^(D)Pro Pro((3S)OH) C 575.5 1.51 98 16 Trp His Tyr(Me)Dab Orn ^(D)Dab Dab Trp Hse tBuGly Ala Ser ^(D)Pro Pro B 557.6 1.89 8317 Leu His Cha Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala alloThr ^(D)ProPro A 528.9 1.35 89 18 Trp His Tyr Dab Orn Dab Dab Trp Dab tBuGly AlaSer ^(D)Pro Pro A 827.4 1.14 90 19 Trp His Cha Dab Orn Dab Dab Trp DabtBuGly Ala Ser ^(D)Pro Pro A 822.4 1.29 82 20 Ile His Tyr Dab Orn^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro Pro B 790.8 1.8 85 21 Ile HisTyr Dab Orn ^(D)Dab Dab Trp Dab Ile Ala Ser ^(D)Pro Pro B 790.7 1.79 9222 Leu His Tyr Dab Orn Dab Dab Trp Dab Chg Ala Ser ^(D)Pro Pro B 803.71.79 90 23 Leu His Tyr Dab Orn ^(D)Dab Dab Trp Dab Chg Ala Ser ^(D)ProPro A 803.8 1.23 91 24 Leu His Trp Dab Orn ^(D)Dab Dab Trp Dab tBuGlyAla Ser ^(D)Pro Pro A 802 1.25 89 25 Leu His Tyr Dab Lys ^(D)Dab Dab TrpDab tBuGly Ala Ser ^(D)Pro Pro A 797.9 1.17 87 26 Leu Trp Tyr Dab Orn^(D)Dab Dab Trp Dab Cha Ala Ser ^(D)Pro Pro A 835.3 1.33 95 27 Leu TrpTrp Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro Pro A 826.7 1.3194 28 Leu Trp Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ala Ser ^(D)Pro ProA 815.3 1.2 95 29 Leu His Tyr Dab Orn ^(D)Dab Dab Trp Dab Trp Ala Ser^(D)Pro Pro A 827 1.15 87 30 Leu His Tyr Dab Orn ^(D)Dab Dab Trp DabtBuGly Ser Ser ^(D)Pro Pro A 798.5 1.18 82 31 Leu Trp Tyr Dab Lys^(D)Dab Dab Trp Dab Cha Ser Ser ^(D)Pro Pro A 850.2 1.3 94 32 Leu TrpTyr Dab Orn ^(D)Dab Dab Trp Dab Cha Ser Ser ^(D)Pro Pro A 843.2 1.32 9433 Leu Tyr Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Asn Ser ^(D)Pro Pro A825.3 1.21 88 34 Leu Trp tBuGly Dab Orn ^(D)Dab Dab Trp Dab Chg Ala Ser^(D)Pro Pro A 803.2 1.26 94 35 Ile Trp tBuGly Dab Lys ^(D)Dab Dab TrpDab Cha Ala Ser ^(D)Pro Pro A 817.3 1.32 90 36 Leu Trp tBuGly Dab Orn^(D)Dab Dab Trp Dab Chg Ser Ser ^(D)Pro Pro A 811.3 1.27 95 37 Leu TrpCha Dab Orn ^(D)Dab Dab Trp Dab tBuGly Ser Ser ^(D)Pro Pro A 818.3 1.3589 38 Leu Tyr Tyr Dab Orn ^(D)Dab Dab Trp Dab tBuGly Tyr Ser ^(D)Pro ProA 849.8 1.26 87 ^(a))Abbreviations of amino acid see listing above^(b))MS: either [M + 2H]²⁺ or [M + 3H]³⁺.

2. Biological Methods

2.1. Preparation of the Peptides

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mg/ml. Stocksolutions were kept at +4° C., light protected.

2.2. Antimicrobial Activity of the Peptides

The selective antimicrobial activities of the peptides were determinedin 96-well plates (Greiner, polystyrene) by the standard NCCLS brothmicrodilution method (National Committee for Clinical LaboratoryStandards 1993. Methods for dilution antimicrobial susceptibility testsfor bacteria that grow aerobically, 3rd ed. Approved standard M7-A6;National Committee for Clinical laboratory standards, Wayne, Pa.) withslight modifications. Inocula of the microorganisms were diluted intoMueller-Hinton II (MH, cation adjusted) broth+0.02% BSA and comparedwith a 0.5 McFarland standard to give appr. 10⁶ colony forming units(CFU)/ml. Aliquots (50 μl) of inoculate were added to 50 μl of MHbroth+0.02% BSA containing the peptide in serial two-fold dilutions. Thefollowing microorganisms were used to determine antibiotic selectivityof the peptides: Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC13883 and Acinetobacter baumannii DSM 30008. Antimicrobial activities ofthe peptides were expressed as the minimal inhibitory concentration(MIC) in μg/ml at which no visible growth was observed after 18-20 hoursof incubation at 35° C.

2.3. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) and centrifuged for 10 min at 2000×g. Compounds(100 μg/ml) were incubated with 20% hRBC (v/v) for 1 h at 37° C. andshaking at 300 rpm. The final erythrocyte concentration wasapproximately 0.9×10⁹ cells/ml. A value of 0% and 100% cell lyses,respectively, was determined by incubation of hRBC in the presence ofPBS containing 0.001% acetic acid and 2.5% Triton X-100 in H₂O,respectively. The samples were centrifuged, the supernatants were 8-folddiluted in PBS buffer and the optical densities (OD) were measured at540 nm. The 100% lyses value (OD₅₄₀H₂O) gave an OD₅₄₀ of approximately0.5-1.0.Percent hemolysis was calculated as follows:(OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

The results of the experiments described in 2.2-2.3 are indicated inTable 2 herein below.

TABLE 2 Minimal inhibitory concentrations (MIC) in Mueller- Hinton brothII and hemolysis Escherichia Klebsiella Acinetobacter coli pneumoniaebaumannii Hemolysis ATCC 25922 ATCC 13883 DSM 30008 at MIC MIC MIC 100μg/ml Ex. [μg/ml] [μg/ml] [μg/ml] [%] 1 0.5 1 2 1 2 0.25 1 1 1 3 0.5 1 23 4 0.5 1 2 5 5 0.5 2 2 0 6 0.5 1 1 3 7 0.5 1 1 1 8 1 4 2 1 9 1 0.5 1n.d. 10 2 1 4 1 11 1 1 2 1 12 1 0.5 2 3 13 2 1 2 2 14 0.25 0.5 1 4 15 11 4 0 16 0.5 2 n.d. 1 17 1 2 4 5 18 2 2 2 0 19 2 1 2 0 20 2 1 2 0 21 1 22 1 22 2 2 4 0 23 2 2 4 3 24 2 1 4 1 25 2 2 2 0 26 1 1 2 1 27 2 1 4 0 282 2 4 1 29 2 2 4 0 30 1 1 2 1 31 1 1 2 1 32 1 0.5 2 3 33 1 1 2 5 34 2 24 1 35 1 1 4 1 36 2 1 4 1 37 2 2 4 1 38 2 2 2 0 n.d.: not determined

The invention claimed is:
 1. A method for the treatment of infectionscaused by gram-negative bacteria or for the treatment or prevention ofthe onset of diseases related to such infections, comprising:administering a compound to a subject in need thereof, wherein saidinfections relate to respiratory diseases or skin or soft tissuediseases or gastrointestinal diseases or eye diseases or ear diseases orCNS diseases or bone diseases or cardiovascular diseases orgenitourinary diseases, or nosocomial infections, or catheter-relatedand non-catheter-related infections, or urinary tract infections, orbloodstream infections; and wherein said compound is a compound of thegeneral formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.2. A method for disinfecting or preserving foodstuffs, cosmetics,medicaments or other nutrient-containing materials against gram-negativebacteria, comprising the step: adding a compound to foodstuffs,cosmetics, medicaments or other nutrient-containing materials, therebydisinfecting or preserving said foodstuffs, cosmetics, medicaments orother nutrient-containing materials, wherein said compound is a compoundof the general formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.3. A method for the manufacture of a medicament to treat infectionscaused by gram-negative bacteria or to treat or prevent the onset ofdiseases related to such infections, comprising the step: formulating acompound with one or more physiologically acceptable carriers, diluents,excipients, or auxiliaries, wherein said infections relate torespiratory diseases or skin or soft tissue diseases or gastrointestinaldiseases or eye diseases or ear diseases or CNS diseases or bonediseases or cardiovascular diseases or genitourinary diseases, ornosocomial infections, or catheter-related and non-catheter-relatedinfections, or urinary tract infections, or bloodstream infections;wherein said compound is a compound of the general formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.4. A method for the manufacture of a disinfectant or preservativeagainst gram-negative bacteria for foodstuffs, cosmetics, medicamentsand other nutrient-containing materials, comprising the step:formulating a compound with one or more physiologically acceptablecarriers, diluents, excipients, or auxiliaries, wherein said compound isa compound of the general formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.5. A method of treating an infection caused by gram-negative bacteria ora disease or disorder associated with an infection caused bygram-negative bacteria, comprising: administering to a subject in needthereof a pharmaceutically acceptable amount of a compound orpharmaceutical composition, wherein said compound is a compound of thegeneral formula (I),cyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof;and wherein said composition contains said compound of the generalformula (I) or a mixture of compounds of general formula (I) and atleast one pharmaceutically inert carrier.
 6. The method of claim 5,wherein said infections are selected from the group consisting ofnosocomial infections, catheter-related and non-catheter-relatedinfections, urinary tract infections, and bloodstream infections.
 7. Themethod of claim 5, wherein said diseases or disorders are selected fromthe group consisting of ventilator-associated pneumonia (VAP),hospital-acquired pneumonia (HAP), healthcare-associated pneumonia(HCAP), cystic fibrosis, emphysema, asthma, pneumonia, epidemicdiarrhea, necrotizing enterocolitis, typhlitis, gastroenteritis,pancreatitis, keratitis, endophthalmitis, otitis, brain abscess,meningitis, encephalitis, osteochondritis, pericarditis, epididymitis,prostatitis, urethritis, surgical wounds, traumatic wounds and burns. 8.A method for the treatment of infections caused by gram-negativebacteria or for the treatment or prevention of the onset of diseasesrelated to such infections, comprising: administering a composition to asubject in need thereof, wherein said infections are related torespiratory diseases or skin or soft tissue diseases or gastrointestinaldiseases or eye diseases or ear diseases or CNS diseases or bonediseases or cardiovascular diseases or genitourinary diseases, ornosocomial infections, or catheter-related and non-catheter-relatedinfections, or urinary tract infections, or bloodstream infections,wherein said composition contains a compound of the general formula (I)or a mixture of compounds of general formula (I) and at least onepharmaceutically inert carrier, wherein general formula (I) iscyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.9. A method for disinfecting or preserving foodstuffs, cosmetics,medicaments or other nutrient-containing materials against gram-negativebacteria, comprising the step: adding a composition to foodstuffs,cosmetics, medicaments or other nutrient-containing materials, therebydisinfecting or preserving said foodstuffs, cosmetics, medicaments orother nutrient-containing materials, wherein said composition contains acompound of the general formula (I) or a mixture of compounds of generalformula (I) and at least one pharmaceutically inert carrier, whereingeneral formula (I) iscyclo[P¹—P²—P³—P⁴—P⁵—P⁶—P⁷—P⁸—P⁹—P¹⁰—P¹¹—P¹²-T¹-T²]   (I) wherein thesingle elements T or P are connected in either direction from thecarbonyl (C═O) point of attachment to the nitrogen (N) of the nextelement and wherein T¹ is ^(D)Pro; T² is Pro; or Pro((3S)OH); P¹ is Leu;Ile; Val; Nva; or Trp; P² is His; Trp; or Tyr; P³ is Leu; Cha; tBuGly;Trp; Tyr; or Tyr(Me); P⁴ is Dab; P⁵ is Orn; or Lys; P⁶ is Dab; ^(D)Dab;or Pip; P⁷ is Dab; P⁸ is Trp; P⁹ is Hse; or Dab P¹⁰ is tBuGly; Ile; Val;Nva; Cha; Chg; or Trp; P¹¹ is Ala; Val; Alb; Ser; Asn; or Tyr; and P¹²is Val; Ser; or alloThr; or a pharmaceutically acceptable salt thereof.10. The method according to claim 1, wherein the compound is selectedfromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 2, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 3, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 4, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 14. The method accordingto claim 5, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 6, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(p)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 7, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 17. The method accordingto claim 8, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 9, wherein the compound is selected fromcyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Nva-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Val-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Alb-Ser-^(D)Pro-Pro-);cyclo(-Val-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Nva-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Alb-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Cha-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-Trp-Leu-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Val-Ala-Val-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Pip-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro((3S)OH)—);cyclo(-Trp-His-Tyr(Me)-Dab-Orn-^(D)Dab-Dab-Trp-Hse-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-alloThr-^(D)Pro-Pro-);cyclo(-Trp-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Trp-His-Cha-Dab-Orn-Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Ile-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Trp-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Trp-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-His-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Cha-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Asn-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ala-Ser-^(D)Pro-Pro-);cyclo(-Ile-Trp-tBuGly-Dab-Lys-^(D)Dab-Dab-Trp-Dab-Cha-Ala-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-tBuGly-Dab-Orn-^(D)Dab-Dab-Trp-Dab-Chg-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Trp-Cha-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Ser-Ser-^(D)Pro-Pro-);cyclo(-Leu-Tyr-Tyr-Dab-Orn-^(D)Dab-Dab-Trp-Dab-tBuGly-Tyr-Ser-^(D)Pro-Pro-);or a pharmaceutically acceptable salt thereof.